The Barshop Institute for Longevity and Aging
Studies, University of Texas Health Science Center at San Antonio, San Antonio,
TX 78245, USA.Department of Pharmacology, University of Texas
Health Science Center at San Antonio, San Antonio, TX 78229, USA.Geriatric Research, Education and Clinical Center and
Research Service, South Texas Veterans Health Care System, San Antonio, TX
78284, USA.

Rapping Down mTORC1 Aids Ailing Muscles

Rapamycin—a bacterial product discovered in soil samples from the
eponymous Rapa Nui, or Easter Island—is a markedly versatile drug.
Clinically, it is used to prevent organ transplant rejection, treat cancer, and
improve angioplasty outcomes; it also increases life span in organisms ranging
from yeast to mice. Now, Ramos and colleagues show its potential for treating
muscle disease caused by mutations in LMNA.

LMNA encodes A-type lamins, intermediate filament proteins that
form the nuclear lamina, a layer just under the nuclear membrane. Different
LMNA mutations cause distinct diseases, but reduced A-type
lamin function is generally linked to skeletal muscle dystrophy and dilated
cardiomyopathy, in which the heart is enlarged and weakened. Mice that lack
Lmna likewise develop these conditions, dying young of
heart problems. Ramos et al. speculated that signaling pathways
involved in muscle remodeling, such as that for the kinase mTOR—the
mammalian target of rapamycin—might be dysregulated in
Lmna−/− mice, contributing to
their problems. mTOR complex 1 (mTORC1) senses information about energy,
nutrients, and stress; in response, it regulates cellular processes such as
protein synthesis and autophagy (in which cellular components are degraded to
reallocate nutrients). The authors found that mTORC1 signaling was
hyperactivated in skeletal and heart muscle in
Lmna−/− mice. Furthermore, the
mTORC1 inhibitor rapamycin decreased mTORC1 signaling, improved skeletal and
cardiac muscle function, and increased the life span of these mice.
Lmna−/− mice also exhibited
defective autophagy, which could be improved by rapamycin. In addition, previous
work showed abnormal aggregation of desmin, which normally forms filaments that
are important for muscle structure, in these mice. Rapamycin decreased these
aggregates.

This study indicates that hyperactive mTORC1 signaling helps to create the
phenotypes of Lmna−/− mice. There are
no effective treatments for the related conditions in humans; this
work—and related findings reported by Choi et al. in
this issue—indicate that rapamycin-related compounds might serve such a
role.

Abstract

Mutations in LMNA, the gene that encodes A-type lamins, cause
multiple diseases including dystrophies of the skeletal muscle and fat, dilated
cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies).
Reduced A-type lamin function, however, is most commonly associated with
skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy
or progeria. The mechanisms underlying these diseases are only beginning to be
unraveled. We report that mice deficient in Lmna, which
corresponds to the human gene LMNA, have enhanced mTORC1
(mammalian target of rapamycin complex 1) signaling specifically in tissues
linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal
of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle
function and enhances survival in mice lacking A-type lamins. At the cellular
level, rapamycin decreases the number of myocytes with abnormal desmin
accumulation and decreases the amount of desmin in both muscle and cardiac
tissue of Lmna−/− mice. In addition,
inhibition of mTORC1 signaling with rapamycin improves defective
autophagic-mediated degradation in
Lmna−/− mice. Together, these
findings point to aberrant mTORC1 signaling as a mechanistic component of
laminopathies associated with reduced A-type lamin function and offer a
potential therapeutic approach, namely, the use of rapamycin-related mTORC1
inhibitors.